ABSTRACT/PROJECT SUMMARY Alzheimer?s disease (AD) is characterized by hyperphosphorylated tau protein which causes impaired axonal transport in neurons. In recent years, multiple researchers have determined that oxidative stress appears to be a significant early event in the pathogenesis of AD in preclinical AD models and in AD patients. We have shown that reducing oxidative stress through quenching of mitochondrial reactive oxygen species (ROS) results in significant improvements in AD pathology in mice. Unfortunately, targeting oxidative stress to date has not been efficacious clinically in mitigating AD pathology. Dietary antioxidants are low potency, require high doses, are potentially toxic at those doses and have not proven clinically effective. There is thus an urgent clinical need to develop potent, stable intracellular antioxidants for the treatment of AD. Polyethylene glycol (PEG)-conjugated hydrophilic carbon clusters (PEG-HCCs) are novel nanoparticle antioxidants that convert superoxide to O2 faster than many single-active-site catalysts. These are also stable, soluble, and non-toxic at moderately high concentrations. We have shown that PEG-HCCs enter cells and preferentially accumulate at or near mitochondria. We hypothesize that PEG-HCCs inhibit action of IL-6 via ROS quenching, which then prevents increased activity of p35 and cdk5, resulting in a normalization of hyperphosphorylated tau and a reduction in AD pathology. The PEG-HCC technology has been awarded multiple patents. Acelerox has obtained the international license to the relevant patents for all fields of use and is set to fully explore and develop the unique properties of this novel nanomaterial in treating Alzheimer?s disease. In this proposal we seek to conduct key animal experiments to establish proof of principle of this novel therapy in animal models of AD. In Aim 1, we will Investigate repeated intranasal administration as a potential route of delivery of PEG-HCCs. In Aim 2, we will perform a proof-of-concept experiment to establish efficacy of PEG-HCC in mouse model of tauopathy. In summary, we will evaluate a novel class of nano-antioxidants, the PEG-HCCs, to effectively reduce ROS in a tau model of AD. We are in the unique position to use these highly active, bioavailable, and selective antioxidant nanomaterials to test the hypothesis that oxidative stress is a viable therapeutic option in treating AD and also begin to assess the mechanisms of improvement in a pre-clinical system. The extensive data generated using these nanoparticles suggest that they are taken up by cells and targeted to mitochondria, the primary source of antioxidants and appear to be well tolerated.